HIV-1 Tat membrane interactions probed using X-ray and neutron scattering, CD spectroscopy and MD simulations

• Published in: Biochimica et biophysica acta 2014-12, Vol.1838 (12), p.3078-3087
• Main Authors: Akabori, Kiyotaka, Huang, Kun, Treece, Bradley W., Jablin, Michael S., Maranville, Brian, Woll, Arthur, Nagle, John F., Garcia, Angel E., Tristram-Nagle, Stephanie
• Format: Article
• Language: English
• Subjects: Lipid bilayer structure cell-penetrating peptide; Low-angle X-ray scattering (LAXS); Membrane pore; Molecular dynamics (MD) simulations; Peptide translocation; Wide-angle X-ray scattering (WAXS)
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2014.08.014

We report the effect on lipid bilayers of the Tat peptide Y47GRKKRRQRRR57 from the HIV-1 virus transactivator of translation (Tat) protein. Synergistic use of low-angle X-ray scattering (LAXS) and atomistic molecular dynamic simulations (MD) indicate Tat peptide binding to neutral dioleoylphosphocholine (DOPC) lipid headgroups. This binding induced the local lipid phosphate groups to move 3Å closer to the center of the bilayer. Many of the positively charged guanidinium components of the arginines were as close to the center of the bilayer as the locally thinned lipid phosphate groups. LAXS data for DOPC, DOPC/dioleoylphosphoethanolamine (DOPE), DOPC/dioleoylphosphoserine (DOPS), and a mimic of the nuclear membrane gave similar results. Generally, the Tat peptide decreased the bilayer bending modulus KC and increased the area/lipid. Further indications that Tat softens a membrane, thereby facilitating translocation, were provided by wide-angle X-ray scattering (WAXS) and neutron scattering. CD spectroscopy was also applied to further characterize Tat/membrane interactions. Although a mechanism for translation remains obscure, this study suggests that the peptide/lipid interaction makes the Tat peptide poised to translocate from the headgroup region. [Display omitted] •Tat causes ~1–2Å average thinning of three membrane mimics.•Local thinning near Tat is ~3Å determined by MD simulations of DOPC/Tat.•Tat increases area/lipid by ~3–5Å2 and softens membranes.•Tat decreases chain order and increases mosaic spread.•A permanent water-filled pore formed by Tat is not supported by this study.